This invention relates to the treatment of diseases associated with viral infection.
Human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome (AIDS), is a retrovirus which selectively infects certain immune system cells, including T4 (CD4+) lymphocytes and CD4+ cells of the monocyte/macrophage lineage. In its advanced stages, HIV infection causes immune system failure and renders the victim susceptible to opportunistic infections and neoplasms. In the absence of effective treatment, the mortality rate for AIDS patients approaches 100% (Fauci, Science 239:617, 1988).
T4 lymphocytes play a central role in many immune system functions, and the cytopathic effect of HIV on infected T4 lymphocytes is thought to be responsible for the devastating effect of HIV infection. Active viral replication usually leads to the death of the host cell. However, in certain host cells the virus does not immediately replicate, and these cells become chronically or latently infected (Fauci, supra). Chronically infected cells express viral proteins at a low level; latently infected cells have an integrated provirus but do not express viral proteins. Although viral replication does not occur in chronically or latently infected cells until the cells are activated, these cells can serve as a reservoir of HIV in the body.
Previous approaches to slowing the progression of HIV infection include the use of antibodies and antibody-like molecules directed against HIV coat proteins, drugs that inhibit viral replication, an cytotoxins targeted to infected cells that express HIV encoded proteins.
Cytotoxic hybrid proteins composed of a cytotoxin fused to part of the CD4 receptor have been proposed as a way to destroy cells expressing HIV encoded proteins. This approach relies on the fact that the HIV envelope protein, gp120, recognizes the CD4 receptor, which is present on T4 lymphocytes and certain cells of the monocyte/macrophage lineage. Thus, a soluble derivative of CD4 might be used to target a cytotoxin to HIV infected cells that express surface gp120. This approach is likely to be most effective against productively infected cells in which HIV is replicating; under these circumstances there is likely to be significant expression of gp120 on the cell's surface. Chaudhary et al. (Nature 335:369, 1988) found that administration of a CD4-Pseudomonas exotoxin hybrid protein to a lymphocytic cell line chronically infected with HIV causes a decrease in overall protein synthesis. Till et al. (Science 242:1166, 1988) found that a CD4-ricin A fusion protein decreases DNA synthesis in cultures of chronically infected H9 cells. In a variation of this strategy, Capon et al. (Nature 337:529, 1989) designed a hybrid protein composed of soluble CD4 and the constant region of an antibody. This molecule is designed to direct immune system response to HIV and the HIV coat protein, gp120. Another molecule of this general type has been shown to activate complement (Traunecker et al., Nature 339:78, 1989).
Human T-lymphotropic retrovius type I (HTLV-I) is associated with adult T-cell leukemia and may play a role in other diseases including tropical spastic paraparesis and HTLV-I associated myelopathy.
Epstein-Barr virus (EBV) is a B lymphotropic human herpes virus. The majority of people infected with EBV develop infectious mononucleosis. EBV is also associated with African Burkitt's lymphoma, anaplastic nasopharyngeal carcinoma, and, in immunocompromised individuals, lymphocytic (usually B-cell) lymphomas.